Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells.

Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.

A precision therapy against cancers driven by KIT/PDGFRA mutations.

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations.

Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians.

Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice.

Short communication: Lower baseline CD4 count is associated with a greater propensity toward virological failure in a cohort of South African HIV patients.

The antiretroviral (ARV) service at Edendale Hospital in Pietermaritzburg, KwaZulu-Natal, South Africa has initiated more than 9,000 adults on therapy since 2004; however, virological outcomes among this patient cohort have not been systematically assessed. We conducted a retrospective chart review of patients initiating ARVs in recent years of the antiretroviral roll-out to determine the efficacy of this program. Clinic records were randomly selected for patients who had initiated ARVs between January 2009 and December 2012. Demographic and virological data were collected. Virological failure was defined as failure to achieve a plasma viral load (VL) <25 copies/ml after 6-12 months of ARV initiation or ≥2 consecutive HIV-RNA VLs ≥400 copies/ml following suppression of <25 copies/ml. Records for 228 individuals were reviewed. Twenty-one (9%) individuals experienced virological failure necessitating a regimen change. The median (interquartile range, IQR) duration of antiretroviral exposure was 19 (11-31) months. Individuals experiencing virological failure did not differ from individuals experiencing success with regards to sex, age, baseline hemoglobin, creatinine, alanine aminotransferase level, or weight (p>0.05) except for having a lower baseline CD4 [median 74 (IQR 31-94) versus 142 (IQR 61-211) cells/µl; p=0.0036 (Mann-Whitney U test)]. No differences were observed between groups in type of ARV regimen, WHO stage at time of ARV initiation, or tuberculosis status. Therefore, using a relatively strict definition of virological failure, we observed that virological success was achievable in over 90% of individuals at the Edendale Hospital ARV clinic. Lower baseline CD4 was associated with greater propensity toward virological failure.

High prevalence of undetected heart failure in long-term care residents: findings from the Heart Failure in Care Homes (HFinCH) study.

AIMS: Diagnosis of heart failure in older people in long-term care is challenging because of co-morbidities, cognitive deficit, polypharmacy, immobility, and poor access to services. This study aimed to ascertain heart failure prevalence and clinical management in this population. METHODS AND RESULTS: A total of 405 residents, aged 65-100 years, in 33 UK care facilities were prospectively enrolled between April 2009 and June 2010. The presence of heart failure was determined using European Society of Cardiology guidelines, modified where necessary for immobility. Evaluation of symptoms and signs, functional capacity, and quality of life, portable on-site echocardiography, and medical record review were completed in 399 cases. The point prevalence of heart failure was 22.8% [n = 91, 95% confidence interval (CI) 18.8-27.2%]; of these, 62.7% (n = 57, 95% CI 59.6-66.5%) had heart failure with preserved ejection fraction and 37.3% had left ventricular systolic dysfunction (n = 34, 95% CI 34.8-40.5%). A total of 76% (n = 61) of previous diagnoses of heart failure were not confirmed, and up to 90% (n = 82) of study cases were new. No symptoms or signs were reliable predictors of heart failure. CONCLUSION: Heart failure was diagnosed in almost a quarter of residents: the prevalence was substantially higher than in other populations. The majority of heart failure cases were undiagnosed, while three-quarters of previously recorded cases were misdiagnosed. Common symptoms and signs appear to have little clinical utility in this population. Early, accurate differential diagnosis is key to the effective management of heart failure; this may be failing in long-term care facilities.

Challenges to the success of HIV and tuberculosis care and treatment in the public health sector in South Africa.

The escalating human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had a significant impact on public health services in resource-limited settings. The province of KwaZulu-Natal in South Africa is estimated to have one of the greatest TB/HIV coinfection burdens on the African continent, coupled with historically low TB treatment success rates. In May 2004, the South African government began providing antiretroviral therapy (ART) for HIV-infected individuals within the public sector. As in many counties, this HIV treatment program was established in parallel with an existing TB treatment service. In 2005, the Integration of TB in Education and Care for HIV/AIDS (iTEACH) Program was launched in KwaZulu-Natal at Edendale Hospital. The goal of iTEACH was to identify barriers to effective treatment and develop support interventions to enable rapid expansion of access to ART and improve ART and TB treatment outcomes within the district served by this facility. In the present article, we discuss challenges to the delivery of TB and HIV care by these separate treatment programs, as well as opportunities to improve both TB treatment and ART outcomes through lessons learned during ART scale-up in the context of the HIV and TB coepidemics.